The goal of this application is to test the general hypotheses that: (1) early and frequent exposure to pathogens accelerates immune system development and 'primes'the immune system to higher levels of baseline immune activity and 2) this chronic immune system activation throughout life results in more rapid immunosenescence and a decline in the ability to defend against novel pathogens.. The Tsimane are Bolivian forager-horticulturalists that live with no electricity, running water, or waste disposal, and have extremely limited access to modern medicine. To accomplish our goal, there are five specific aims of this competitive revision to the existing R01 "The Human Life Course and the Biodemography of Aging". Aim 1 is to measure the levels of cytokines, inflammatory biomarkers, and immunoglobulins in Tsimane sera. Aim 2 is to test cytokine responses during in vitro stimulation of fresh whole-blood with bacterial, viral, and helminthic antigens. Aim 3 is to quantify in vivo lymphocyte and T-cell populations with flow cytometry to characterize cellular components of immunity by age and sex. Aim 4 is to test a series of predictions derived from the above two hypotheses. Aim 5 is investigate the relationships between disease states, functional status, mortality and immune system function. The addition of this project will allow us to build a cross-sectional and longitudinal profile of a large sample of adults to model interactions between infection, immune system development and immunosenescence in a population that reached maturity in a pre-modern, highly infectious environment. We combine four methods to investigate immune responsiveness to infection: 1) physician exams combined with laboratory analysis to diagnosis infections by type;2) measurement of serum cytokines, inflammatory markers and immunoglobulins;3) In vitro whole blood challenges with common and novel helminthic, viral and bacterial antigens;4) flow cytometry to identify number and proportions of memory- and senescent- T and B cell phenotypes.). As the Tsimane are undergoing rapid change, we will also be able to assess within-population variance by examining the effects of acculturation on immunity at the community and individual level. We will also compare our results to those obtained in the U.S. and other countries, to assess the impacts of the infectious burden of disease on immunity over the life course. PUBLIC HEALTH RELEVANCE: This renewal will provide detailed information on infectious disease and immune responsiveness over the life course in a pre-modern population of forager-horticulturalists of South America experiencing a high pathogen burden. Investigation of immune system development and senescence in a large sample of older adults can reveal unique insights about how the immune system responds to the intensity of pathogen exposure and how increased activation of the immune system throughout life can affect the rate of immunosenesence. Since much of the world still lives in developing countries, with co-infection of parasites, viruses and bacteria, the results of this research, combined with measures of aging and disease in other populations such as the U.S. and Indonesia, will help eludicate trends in disease epidemiology across environmental and social contexts.